C. Cordova

Association between low-grade disseminated intravascular coagulation and endotoxemia in patients with liver cirrhosis

BACKGROUND & AIMS Hyperfibrinolysis may complicate the clinical course of liver cirrhosis. The aim of this study was to evaluate if, in cirrhosis, hyperfibrinolysis is primary or secondary to intravascular clotting activation and if endotoxemia is associated with activation of clotting and/or the fibrinolytic system. METHODS Clotting, fibrinolytic indexes, and endotoxemia were studied in 41 cirrhotic patients and 20 healthy subjects. RESULTS Twenty-seven cirrhotic patients (66%) had high plasma levels of prothrombin fragment F1 + 2, a marker of thrombin generation. Nineteen patients had elevated values of D-dimer, a marker of fibrinolysis in vivo. All patients with high values of D-dimer also had high values of prothrombin fragment F1 + 2. Endotoxemia was elevated in patients with severe liver failure and significantly correlated to prothrombin fragment F1 + 2. Thirty patients were treated for 7 days either with standard therapy (n = 15) or with standard therapy plus nonabsorbable antibiotics (n = 15). Although standard therapy did not significantly change laboratory indexes, a significant reduction of endotoxemia, prothrombin fragment F1 + 2, and D-dimer was found in those patients who received the combined treatment. CONCLUSIONS This study shows that, in cirrhotic patients, hyperfibrinolysis is not a primary phenomenon but occurs as a consequence of clotting activation and that endotoxemia might play a pathophysiological role.

Bleeding time in patients with cirrhosis: relation with degree of liver failure and clotting abnormalities

Patients with cirrhosis suffer from a complex haemostatic disturbance, due to abnormalities in clotting and fibrinolytic system activation and in primary haemostasis. The latter is indicated by a prolongation of bleeding time, which is a reliable indicator of platelet function in vivo. To further assess the relationship between bleeding time, degree of liver failure and clotting abnormalities in patients with cirrhosis, bleeding time was investigated in a prospective study of 70 consecutive patients with cirrhosis diagnosed by liver-needle biopsy, of whom 19 belonged to Child-Pugh class A, 29 to B and 22 to C. Among patients with cirrhosis, 40% had an abnormal bleeding time (> 10 min), and 42% had a platelet count < 100,000/microliters. Patients with severe liver failure (class C) had a lower platelet count and a more prolonged bleeding time than patients in classes A and B. Bleeding time was significantly inversely correlated to platelet count, fibrinogen, prothrombin activity and packed cell volume, and directly correlated to serum bilirubin and D-dimer. However, in class C patients, only a significant inverse correlation between bleeding time and fibrinogen was observed. These findings indicate that in cirrhosis worsening of platelet function is closely related to the degree of liver failure. The inverse correlation between bleeding time and fibrinogen indicates that a low value of this clotting parameter may account in part for platelet dysfunction.

Simvastatin reduces monocyte-tissue-factor expression type IIa hypercholesterolaemia

Inhibitors of 3-hydroxy-methyl-glutaryl coenzyme A reductase have been shown to reduce cardiovascular events in patients with raised and average serum cholesterol. It is unclear whether this effect is attributable solely to reduction of serum cholesterol or to other mechanisms. We analysed whether simvastatin directly affects expression of monocyte tissue factor (TF). After 4 weeks of diet alone (fat intake <30% of total calories, cholesterol <300 mg daily, polyunsaturated/ saturated fatty acids ratio=1·0) (run-in phase), 24 patients (12 men and 12 women; mean age 52 [SD 8] range 35–70 years) with polygenic hypercholesterolaemia were randomised to simvastatin (20 mg daily) or to continue diet for 8 weeks. Before and after treatment, expression of TF antigen and activity as well as the circulating concentrations of prothrombin fragment F1+2, a marker of thrombin generation, were measured. Nine parts of blood were mixed in a pre-cooled vacutainer (Becton Dickinson Vacutainer System, France) with 1 part of 3·8% sodium citrate and centrifuged for 20 min at 2000 g at –4oC. Plasma samples for measurement of F1+2 (Enzygnost F1+2, Behringwerke ag, Marburg) were stored at –40oC. To measure monocyte TF, peripheral blood mononuclear cells were isolated from heparinised venous blood (2 10 cells/mL) and incubated for 6 h with 0·4 ng/mL lipopolysacchariae (Escherichia coli [OB11:B4, Sigma, St Louis, MI, USA). In the lysate of the cells, TF antigen was measured by an ELISA test (Imubind Tissue Factor ELISA kit, American Diagnostica Inc, Greenwich, CT) and TF activity was determined by measuring monocyte procoagulant activity with one stage clotting assay. Hypercholesterolaemic patients showed significantly higher concentrations of F1+2 (mean [SD] 2·2 [0·4] vs 0·6 [0·3] nmol/L: p<0·0001), TF antigen (median [range] 63 [41–89] vs 16 [10–39] pg/2 10 monocytes; p<0·0001) and activity (median [range] 31 [20–44] vs 9 [4–20] U/2 10 monocytes; p<0·0001) than 24 controls matched for age and sex (unpaired t test and Mann-Whitney U test). Patients randomised to diet or diet plus simvastatin had similar clinical (not shown) and laboratory variables (table). In patients continuing the follow-up by diet alone, no significant changes of the variables were observed. In patients taking simvastatin there was a significant decrease of cholesterol, LDL cholesterol, F1+2, and monocyte TF expression. Comparing the diet and simvastatin groups at the end of the treatment period, simvastatin group showed significantly lower concentrations of F1+2, TF antigen, and activity. This study shows that simvastatin reduces the expression of monocyte TF, an effect which may explain the reduction of cardiovascular events elicited by simvastatin.

Relation between lupus anticoagulant and splanchnic venous thrombosis in cirrhosis of the liver.

While angiographic studies have indicated that splanchnic venous thrombosis rarely occurs in patients with cirrhosis of the liver, a postmortem study has shown that it may occur in up to a fifth.1 We have shown that patients with cirrhosis have lupus anti-coagulant, which predisposes to venous and arterial thrombosis.2 In this study we determined whether splanchnic venous thrombosis is associated with lupus anticoagulant in patients with cirrhosis. From October 1990 to November 1991, 73 consecutive patients (43 men) aged 35-77 with cirrhosis of the liver that had been diagnosed by liver biopsy entered the study. Liver failure was categorised as mild, moderate, or severe according to Child-Pughs classification. Twenty nine patients had markers of hepatitis B virus infection, 30 had markers of hepatitis C virus infection, 11 had a history of alcohol misuse, and in three the cause of cirrhosis was …

Bleeding time does not predict gastrointestinal bleeding in patients with cirrhosis

BACKGROUND/AIMS Bleeding time, a laboratory test which explores primary hemostasis, may be prolonged in cirrhosis, but whether abnormal bleeding time identifies patients with cirrhosis who are at risk of bleeding has never been investigated. The aim of this study was to analyze the relationship between bleeding time and the risk of gastrointestinal bleeding. METHODS Eighty consecutive patients with liver cirrhosis (47 males, 33 females; age, 60 +/- 9 years; range 31 to 83 years) and esophageal varices were enrolled in the study. RESULTS In the whole series of patients bleeding time was 11 +/- 6 min; it increased as the degree of liver deficiency increased, from low to severe (p = 0.007). During 14 +/- 9 (median (range): 12 (1-34) months of follow-up, 28 (35%) patients experienced gastrointestinal bleeding. They had a longer bleeding time, higher incidence of previous bleeding, more severe liver failure and larger variceal size than patients who did not bleed. However, multivariate analysis (Coxs model) showed that only previous bleeding, liver failure and variceal size were independently associated with bleeding. Similar data were obtained in patients with moderate-severe liver insufficiency (B and C degree according to Child-Pughs classification). In patients who had never bled (n = 54), the severity of liver failure and variceal size were independent predictors of bleeding. CONCLUSIONS This study shows that bleeding time is not a predictor of gastrointestinal bleeding in patients with cirrhosis.

Prognostic value of clotting and fibrinolytic systems in a follow-up of 165 liver cirrhotic patients☆

One hundred sixty-five patients with cirrhosis diagnosed by needle liver biopsy were followed for 2 years to evaluate the relation between clotting factors and survival. Patients with spontaneous bacterial peritonitis, hepatic carcinoma, and cholestatic liver diseases were excluded. Patients were classified as A (n = 34), B (n = 75), or C (n = 56) according to Child-Pugh criteria. During the follow-up 45 patients died of liver failure or gastrointestinal hemorrhage. Nonsurvivor patients had significantly higher values of bilirubin and D-dimer, a marker of fibrinolysis in vivo, lower values of albumin, prothrombin activity, fibrinogen, prekallikrein, factor VII, and a more prolonged activated partial thromboplastin time than survivors. All these variables and Child-Pugh classification were significantly associated with survival in a univariate analysis. Multivariate analysis (Coxs model) showed that only prekallikrein and factor VII were independently predictors of survival. Ninety-three percent of patients with prekallikrein values < 32% died within 32 months of follow-up, whereas factor VII < 34% identified 93% of patients who died within 10 months of follow-up. This study suggests that factor VII is an early predictor of survival and may be a useful test to better identify cirrhotic patients who should be candidates for liver transplantation.

Lipoprotein(a) serum levels in patients affected by chronic obstructive pulmonary disease

A recent study has suggested that symptoms of chronic bronchitis predict the risk of coronary disease independently of the known major cardiovascular risk factors. High serum levels of lipoprotein(a) (Lp(a)) have also been considered as an independent risk factor for coronary heart disease. Therefore, the aim of the present study was to investigate the behaviour of Lp(a) in patients affected by chronic obstructive pulmonary disease (COPD). Serum levels of total-cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides, apolipoprotein (Apo) B-100, and Lp(a) were measured in 90 COPD patients and in 90 normal subjects matched for age, sex and smoking habit. COPD patients showed lower serum levels of Apo B-100 (P<0.0001) and Lp(a) (P<0.003) compared to controls. Conversely, TC, HDL-C, LDL-C and triglycerides were similar between patients and controls. No significant differences were found in Apo B-100 and Lp(a) levels of patients either undergoing different therapeutic regimens, or with different smoking habits. A significant correlation between Apo B-100 and Lp(a) (rho=0.433, P<0. 0001) was also observed. In conclusion, COPD patients do not show an atherogenetic lipid pattern and their increased risk of coronary disease could be attributable to different factors, such as the ongoing hypercoagulability state often associated with COPD.

Soluble P-Selectin and Proinflammatory Cytokines in Patients with Polygenic Type IIa Hypercholesterolemia

Plasma soluble P-selectin (sP-selectin), β-thromboglobulin (β-TG), von Willebrand Factor (vWF), prothrombin factor 1+2 (F1+2), IL-6 and IL-1β levels were analyzed in 35 consecutive patients with polygenic type IIa hypercholesterolemia (HC) and 35 age- and sex-matched healthy subjects. sP-selectin (p < 0.005), β-TG (p < 0.05) and IL-1β (p < 0.02) levels were higher in HC patients than healthy subjects whereas no significant difference was observed for vWF. sP-selectin directly correlated with β-TG (p < 0.05) and IL-1β levels (p < 0.005), but not with the other variables analyzed. A direct correlation was observed between F1+2 and IL-6 (p < 0.05), total cholesterol (p < 0.05) or LDL cholesterol (p < 0.05). We conclude that HC is associated with an increase of plasma sP-selectin levels, and that sP-selectin may be considered as a marker of in vivo platelet activation in type IIa polygenic HC. The correlations observed among the variables analyzed in the study suggest that proinflammatory cytokines might play a role in the prothrombotic state often associated with HC.

1-Year survey of patients with advanced liver cirrhosis : prognostic value of clinical and laboratory indexes identified by the cox regression model

The relation between coagulation indexes and survival rate was studied and analyzed in 46 patients with advanced liver cirrhosis (grade B and C Child-Pugh Classification), during a follow-up of 1 year. Twenty-four patients (52%) died of liver failure or fatal haemorrhage within 12 months of follow-up. Prothrombin activity, fibrinogen, fibrin(ogen) degradation products, prekallikrein and factor VII, serum bilirubin, and the degree of liver insufficiency, scored by Child-Pugh classification, proved to be significantly correlated with survival by univariate analysis. A multivariate survival analysis (Cox regression model) disclosed two variables, prekallikrein and factor VII, that predicted survival. The rate ratios of death increased to 2.8 and 7.6 with values of prekallikrein < 26% and factor VII < 39%, respectively. This study shows that some simple laboratory tests exploring the clotting system may identify patients with poor prognosis in severe liver failure.

Inhibition of cyclooxygenase-independent platelet aggregation by low vitamin E concentration

Platelet aggregation induced by threshold concentrations of agonists such as collagen, PAF or epinephrine was inhibited in vitro by 100 microM aspirin but was restored by stimulating platelets with high concentrations of collagen, PAF or by a combination of epinephrine and PAF. Incubating aspirin-treated platelets with 50-100 microM vitamin E or vitamin E acetate inhibited platelet aggregation by high concentrations of collagen and PAF and by the combination of epinephrine and PAF; platelet thromboxane A2 formation was less than 10% in samples incubated with 100 microM aspirin. Apyrase, added to aspirin-treated platelet, did not influence platelet aggregation induced by epinephrine and PAF. The present study suggests that concentrations of vitamin E as low as 50-100 microM inhibit cyclooxygenase-independent platelet aggregation when combined with an inhibitor of the arachidonate pathway.